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Methodology

Hand-searches of Published Literature (Primary Sources)Hand-searches of Published Literature (Secondary Sources)Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

For the 2010 guideline update, the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) Update Committee completed a systematic review and analysis of data published since 2007. The Update Committee's literature review focused attention on available systematic reviews and meta-analyses of published phase III randomized controlled trials (RCTs) of erythropoiesis-stimulating agents (ESAs). Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. Searches of the English-language literature from January 1, 2007 to January 31, 2010, were conducted to address each of the recommendation domains in the 2007 update. Relevant practice guidelines from other oncology and national organizations were identified through a search of MEDLINE and of the National Guideline Clearinghouse Web site.

Literature Search Strategy

For the 2010 guideline update, pertinent published information was reviewed to address each of the guideline questions. One meta-analysis using individual patient data and six comprehensive systematic reviews and meta-analyses of RCTs served as the primary evidentiary basis for this update. An additional 13 papers met the inclusion criteria and reported results from RCTs that were not included in any of the meta-analyses or systematic reviews. Supplementary searches of the MEDLINE database (National Library of Medicine, Bethesda, MD) were conducted to identify relevant information (January 2007 through January 2010) from additional published RCTs, systematic reviews, meta-analyses, and practice guidelines for this update. A series of searches was conducted using the medical subject headings or text words "erythropoietin, recombinant," "epoetin alfa," "epoetin beta," "darbepoetin alfa," and "neoplasms," and variants thereof. (Details of the searches can be obtained from guidelines@asco.org on request.) Search results were limited to human studies and English-language articles. Search terms can be found in Data Supplement DS13 (see "Availability of Companion Documents" field). Only trials that reported clinical outcomes in nonpediatric populations were included in the systematic review. Trials were excluded if they only reported hematologic response rates and/or hemoglobin (Hb) concentration. Publications were included if they reported retrospective analyses of previously published RCTs. Extraction and review of quality-of-life (QOL) data were limited to studies and systematic reviews that included a control arm not treated with an ESA, reported QOL results separately for each arm, and reported overall QOL scores (in addition to any subscale scores that may have been reported) from standardized, validated QOL instruments. Editorials, letters, and commentaries were excluded from consideration, as were systematic reviews and meta-analyses that were limited to single agents, on the basis of the U.S. Food and Drug Administration's position that available ESAs are members of the same pharmacologic class. The Cochrane Library was searched for available systematic reviews and meta-analyses with the phrases "erythropoietin," "epoetin," "darbepoetin," "cancer," and "malignancies." Directed searches on the basis of the bibliographies of primary articles were also performed. Finally, Update Committee members and ASCO staff contributed articles from their personal collections.

Number of Source Documents

The literature search conducted for this guideline update yielded one new individual patient data meta-analysis, six new literature-based meta-analyses and/or systematic reviews of randomized controlled trials (RCTs), and an additional 13 publications reporting results from RCTs that were not included in any of the meta-analyses or systematic reviews.

Methods Used to Assess the Quality and Strength of the Evidence

Expert Consensus (Committee)

Rating Scheme for the Strength of the Evidence

Not applicable

Methods Used to Analyze the Evidence

Review of Published Meta-AnalysesSystematic Review with Evidence Tables

Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations

Expert Consensus

Description of Methods Used to Formulate the Recommendations

The American Society of Clinical Oncology Clinical Practice Guidelines Committee convened the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) Update Committee to lead the 2010 update. The Update Committee met via a series of teleconferences to review evidence collected from the systematic review and make revisions to the guideline recommendations as warranted. A draft of the guideline document was developed by a steering group of the Update Committee and ASCO and ASH staff.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation

External Peer ReviewInternal Peer Review

Description of Method of Guideline Validation

The guideline was submitted to Journal of Clinical Oncology for peer review. It also underwent peer review before acceptance by Blood. Feedback from external reviewers was also solicited. The guideline was reviewed and approved by the entire Update Committee, American Society of Clinical Oncology (ASCO's) Clinical Practice Guidelines Committee, American Society of Hematology (ASH's) Committee on Practice, and ASH's Subcommittee on Quality of Care. The guideline was approved by the ASCO Board of Directors on July 7, 2010 and by the Executive Committee of the ASH on July 14, 2010.

Recommendations

Major Recommendations

General Recommendations

2010 Recommendation

It is recommended that before any decision regarding use of erythropoiesis-stimulating agents (ESAs) is made, appropriate history, physical examination, and diagnostic tests be conducted to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy.

At a minimum, this would include:

Thorough drug exposure history

Review of a peripheral-blood smear (and in some cases, a bone marrow examination)

Analyses, where indicated, for iron, folate, or vitamin B12 deficiency

Consideration must be given to demonstrated risks of thromboembolism (see Recommendation IV), the possibility of death, and minimizing ESA use, particularly in patients with malignancy being treated with curative intent.

Special note. Although the U.S. Food and Drug Administration (FDA) label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent (see "Literature update and discussion: weighing harms versus benefits" in the original guideline document), no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent. Determination of the goal of treatment requires clinical judgment in many cases.

Special Commentary on the Comparative Effectiveness of Epoetin and Darbepoetin

2010 Recommendation

This recommendation remains the same as in 2007. On the basis of a comprehensive systematic review comparing outcomes of epoetin and darbepoetin in patients with chemotherapy-induced anemia and on the basis of identical indications, warnings, and cautions in the relevant FDA-approved package inserts, the Update Committee considers these agents to be equivalent with respect to effectiveness and safety.

The use of epoetin or darbepoetin is recommended as a treatment option that may be considered for patients with chemotherapy-associated anemia and a Hb concentration that has decreased to less than 10 g/dL to decrease transfusions. Red blood cell transfusions (RBC) transfusion is also an option, depending on the severity of the anemia or clinical circumstances.

An optimal level at which to initiate ESA therapy in patients with anemia with an Hb between 10 and 12 g/dL cannot be definitively determined from the available evidence. Under these circumstances, whether or not to initiate ESA treatment should be determined by clinical judgment, consideration of the risks and benefits of ESAs, and patient preferences (see Recommendations I and IV). RBC transfusion is an option when warranted by clinical conditions.

Thromboembolic Risk

2010 Recommendation

This recommendation remains the same as in 2007. Clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin is prescribed. Randomized controlled trials (RCTs) and systematic reviews of available RCTs demonstrate an increased risk of thromboembolism in patients receiving epoetin or darbepoetin. Specific risk factors for thromboembolism have not been defined in these trials; therefore, clinicians should use caution and clinical judgment when considering use of these agents. Established, general risk factors for thromboembolic events include history of thromboses, surgery, and prolonged periods of immobilization or limited activity. Some diseases and treatment regimens have also been associated with higher risk of venous thromboembolic events (see the literature update and discussion in the original guideline document).

Starting and Modifying Doses

2010 Recommendation

It is recommended that starting and modifying doses of ESAs follow FDA guidelines:

FDA-approved starting dose of epoetin is 150 U/kg three times a week or 40,000 U weekly subcutaneously.

Dose modification should follow FDA recommendations as outlined in the table below.

Discontinue ESA treatment when chemotherapy concludes.

Evidence does not exist to support improved effectiveness or safety with alternative starting doses, dose schedules, or dose modifying schedules.

Table. ESA Adult Dosing

Epoetin Alfa

Darbepoetin Alfa

Dose and Modification

Initial Dose

Initial dose* of 150 U/kg SC TIW

Initial dose* of 40,000 U SC weekly

Initial dose* of 2.25 micrograms/kg SC weekly

Initial dose* of 500 micrograms SC Q3W

Dose Increase

Increase dose to 300 U/kg TIW if no reduction in transfusion requirements or increase in Hb after 4 weeks of therapy to achieve and maintain lowest Hb level sufficient to avoid need for RBC transfusion.

Increase dose to 60,000 U SC weekly if no increase in Hb by ≥1 g/dL after 4 weeks of therapy, in the absence of a RBC transfusion to achieve and maintain lowest Hb level sufficient to avoid need for RBC transfusion.

Increase dose to 4.5 micrograms/kg if there is <1 g/dL increase in Hb after 6 weeks.

This recommendation remains the same as in 2007. Continuing epoetin or darbepoetin treatment beyond 6 to 8 weeks in the absence of response (e.g., a <1 to 2 g/dL increase in Hb or no diminution of transfusion requirements) does not seem to be beneficial, assuming an appropriate dose increase has been attempted in non-responders as per the FDA-approved label, and ESA therapy should be discontinued. Patients who do not respond should be investigated for underlying tumor progression, iron deficiency, or other etiologies for anemia.

Hb Target

2010 Recommendation

Hb can be increased to the lowest concentration needed to avoid transfusions, which may vary by patient and condition.

Qualifying statement. An optimal target Hb concentration cannot be definitively determined from the available literature. Modification to reduce the ESA dose is appropriate when Hb reaches a level sufficient to avoid transfusion or the increase exceeds 1 g/dL in any 2-week period to avoid excessive ESA exposure (see Recommendation V), considering the risks of ESAs (see Recommendation I). Specific dose-reduction recommendations are provided in the table above.

Iron Monitoring and Supplementation

2010 Recommendation

This recommendation remains the same as in 2007. Baseline and periodic monitoring of iron, total iron binding capacity, transferrin saturation, or ferritin levels and instituting iron repletion when indicated may help to reduce the need for ESAs, maximize symptomatic improvement for patients, and determine the reason for failure to respond adequately to ESA therapy. There is inadequate evidence to specify the optimal timing, periodicity, or testing regimen for such monitoring. Although iron replacement is generally recommended to augment response for ESA recipients with iron deficiency, there is inadequate evidence to consider the use of intravenous iron as a standard of care.

Anemia in Patients Not Receiving Concurrent Chemotherapy

2010 Recommendation

It is recommended that ESAs not be used in treatment of anemia associated with malignancy in patients who are not receiving concurrent myelosuppressive chemotherapy. Use of ESAs in patients with lower risk MDS to avoid transfusions is an exception to this recommendation.

Treatment of Anemia in Patients with Nonmyeloid Hematological Malignancies Who Are Receiving Concurrent Chemotherapy

2010 Recommendation

This recommendation remains the same as in 2007. Physicians caring for patients with myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia are advised to begin treatment with chemotherapy and/or corticosteroids and observe the hematologic outcomes achieved solely through tumor reduction before considering epoetin. If an increase in Hb is not observed after chemotherapy, treatment with epoetin or darbepoetin for patients with myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia, who are being treated with palliative intent and who are experiencing chemotherapy-associated anemia, should follow Recommendations I through VIII. Particular caution should be exercised in the use of epoetin or darbepoetin concomitant with chemotherapeutic agents and diseases where risk of thromboembolic complications is increased (see Recommendation IV). Blood transfusion is also a therapeutic option.

Special note. Although the FDA label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent (see "Literature update and discussion: weighing harms versus benefits" in the original guideline document), no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent. Although patients with multiple myeloma and chronic lymphocytic leukemia often respond to first- or subsequent-line therapy, because these malignancies recur in most patients, determining the treatment intent requires clinical judgment of an individual patient's circumstances.

Clinical Algorithm(s)

An algorithm for the use of erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia is provided as a companion document (see "Availability of Companion Documents").

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of evidence supporting the recommendations is not specifically stated.

The updated recommendations are supported primarily by one meta-analysis using individual patient data and six comprehensive systematic reviews and meta-analyses of randomized controlled trials (RCTs).

Individual patient preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia in these patients. The Update Committee cautions against ESA use under all other circumstances.

Clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin is prescribed. Randomized controlled trials (RCTs) and systematic reviews of available RCTs demonstrate an increased risk of thromboembolism in patients receiving epoetin or darbepoetin.

Qualifying Statements

Qualifying Statements

The American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) practice guidelines reflect expert consensus on the basis of clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a guideline was submitted for publication. Guidelines are not continually updated and may not reflect the most recent evidence. Guidelines address only the topics specifically identified in the guideline and are not applicable to interventions, diseases, or stages of disease not specifically identified. Guidelines cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances and preferences. ASCO/ASH guidelines describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO and ASH assume no responsibility for any injury or damage to persons or property arising out of or related to any use of the ASCO/ASH guidelines or for any errors or omissions.

Special Commentary on Erythropoiesis-Stimulating Agents (ESAs), Survival, and Tumor Response

Since the publication of the 2007 guideline, the results of several randomized controlled trials (RCTs) have either been published or become available in the public domain, with some additional studies reporting adverse health effects associated with ESA use in patients with cancer. In response, the labels for ESAs were revised by the manufacturers and approved by the U.S. Food and Drug Administration (FDA) to alert physicians to shortened survival and/or increased risk of tumor progression or recurrence in eight RCTs involving patients with cancer of the head and neck, breast, or uterine cervix; non–small-cell lung cancer; or various lymphoproliferative malignancies or mixed nonmyeloid cancers.

Six of these RCTs were abstracted in detail in the 2007 guideline update. This commentary briefly summarizes the results of several RCTs that evaluated survival or tumor progression since the 2007 guideline update. Virtually all studies reported here demonstrated responses to ESA therapy measured by increases in hemoglobin (Hb) or transfusion avoidance as anticipated. Common limitations of some of the trials recently completed are early trial closure, insufficient numbers of participants, and/or inadequate follow-up to determine adverse events (e.g., tumor progression and survival). This makes interpretation of the results extremely challenging because the studies are ultimately underpowered to detect the outcomes of interest (survival), thus masking potentially true risks or true benefits of ESA therapy. See the original guideline document for the literature review on these studies.

The American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) Update Committee was assembled in accordance with ASCO's Conflict of Interest Management Procedures for Clinical Practice Guidelines ("Procedures," summarized at www.asco.org/guidelinescoi). Members of the Update Committee completed ASCO's disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the guideline. Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony. In accordance with the Procedures, the majority of the members of the Update Committee did not disclose any such relationships.

ASH reviewed each potential member of the guideline Update Committee before beginning the guideline work to determine whether conflicts of interest were present. Each potential member completed a form on which he or she was asked to note relationships with any drug or device company and to provide the name of the company, drug, or device involved; the nature of the conflict; and relevant dates. As needed, staff conferred with the potential Update Committee members to discuss the relationship(s) and to clarify the presence of any conflict. After discerning that a member would not be conflicted, his or her service on the Committee was approved. The rationale behind ASH's conflict of interest policy is to assure the integrity of ASH and to avoid bias arising from conflicts of interest by the individuals involved with activities. During the final stages of guideline preparation, conflict of interest forms were updated. An inadvertent omission of disclosure was noted by a Committee member (J.L.S., for a single event). The nature of the relationship was clarified, and the Update Committee co-chairs and the chair of the ASH Quality of Care Subcommittee reviewed the contributions of the individual and determined that they were not biased by conflicted interests.

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the "Author Disclosure Declaration" and the "Disclosures of Potential Conflicts of Interest" section in the original journal of publication.

American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Guideline summary. 2010 Nov. 5 p. Electronic copies: Available in PDF from the ASCO Web site.

American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Slide set. 2010. 30 p. Electronic copies: Available in PDF and Power Point from the ASCO Web site.

American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. ESA adult dosing table. 2010. 1 p. Electronic copies: Available in PDF from the ASCO Web site.

What to know: the ASCO/ASH guideline on epoetin and darbepoetin treatment for adults with cancer. Patient guide. 2010 Oct. Available from the ASCO Web site.

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

NGC Status

This NGC summary was completed by ECRI on May 16, 2003. The information was verified by the guideline developer on June 25, 2003. This summary was updated by ECRI on January 29, 2007, following the U.S. Food and Drug Administration advisory on erythropoiesis stimulating agents. This summary was updated by ECRI Institute on July 9, 2007, following the FDA advisory on erythropoiesis stimulating agents. This NGC summary was updated by ECRI Institute on February 19, 2008. The updated information was verified by the guideline developer on February 20, 2008. This summary was updated by ECRI Institute on August 15, 2008 following the U.S. Food and Drug Administration advisory on Erythropoiesis Stimulating Agents (ESAs). This summary was updated by ECRI Institute on April 1, 2010 following the U.S. Food and Drug Administration advisory on Erythropoiesis-Stimulating Agents (ESAs). This NGC summary was updated by ECRI Institute on March 21, 2011.

Copyright Statement

This summary is based on the original guideline, which is subject to the American Society of Clinical Oncology's copyright restrictions.

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